L'inattivazione dei Silvano Rossinivecchiosito.istitutotumori.mi.it/istituto/documenti/...La...

La Sicurezza Trasfusionale – Milano, 8 Aprile 2009

Silvano [email protected]

Servizio di Immunomatologia e Medicina Trasfusionale

L'inattivazione dei patogeni: tecnologie e

prospettive

mailto:[email protected]

Inattivazione Patogeni – Milano, 8 Aprile 09

S. Rossini

Il percorso di oggi

I patogeni emergenti in Medicina Trasfusionale(Massimo Clementi

Infezione occulta da Virus dell’Epatite B(A. Tagger)

I patogeni storici riemergenti(G. Gesu)

Cosa possiamo fare ?


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Transfusion safety

recruit

screen donor

collect & prepare

infection disease test

product

Pre-tranfusion testing

Medical decision to transfuse

Issue

Administer(bedside)

Monitor & evaluate

processW. Dzik, 2003


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Il problema infettivo

Le tecnologie per l’inattivazione

Il rapportocosto/beneficio


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New ed emerging pathogensA risk that current safety

Measures cannot eliminate

Screening limitationsGaps in current defenses exits,due to the window period and

limited screening sensitivity


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Know pathogensRoutine testing coversonly a limited numeber





LeukocytesResidual cells and cytokines

can cause harmful post-transfusion reactions


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BacteriaThe most frequent

transfusion-transmitted infection

Know pathogensRoutine testing coversonly a limited numeber





LeukocytesResidual cells and cytokines

can cause harmful post-transfusion reactions


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Il rischio sepsi

Prevalence of contaminated platelets:1:2500 random platelet concentrates1:5000 singol donor platelets (SDP)

Risk of sepsis1:50000 with SDP

Castro E. et al., Trasfus Med 3005, Palavecino El et al., Transfusion 2006


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Il “Challenge”

Agenti infettivi nuovi continuano ad emergere

Agenti infettivi nuovi migrano rapidamente da ospiti non-umani all’uomo

L’identificazione di patogeni emergenti, la comprensione dell’epidemiologia, lo sviluppo di test diagnostici e la protezione del sangue richiede tempo


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Le tecnologie per l’inattivazione

Il rapportocosto/beneficio


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Acellular Products Cellular Products

Plasma and derivatives

Platelets Red Cells

Tecnique targeting nucleic acid

Tecnique targeting membrane

Solvent-detergent Yes No No

Methylene Blue Yes No No


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La La (complessa) biologia piastrinica biologia piastrinica


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L’idea Gli acidi nucleici come bersaglio per bloccare la proliferazione dei patogeni

Principi fisico -chimici Biologia

Modalità operative

Inattivazione


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Le tecnologie proposte

Intercept – CerusMirasol – Navigant

Macopharma – Theraflex


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DNA or RNAof pathogen

Meccanismo d’ Azione di S-59

S-59

IntercalationPermanent

Crosslinking

UVA Activation

Intercept (I)


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Collected Collected PlateletsPlatelets

Integrated Container Set

Step 2Step 2IlluminationIllumination

UVA Illumination Device

Concentrati piastrinici

Step 1 Step 1 S-59S-59

Step 3Step 3CADCAD

Step 4Step 4Final StorageFinal Storage

SCDSCD

Intercept (II)


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Intercept: utilizzo clinico

Marchio CE3 trial clinici in Europa (euroSPRITE)

166 pazienti Comparable post transfusion platelet count

incrementTrial SPRINT

645 pazienti4719 trasfusioniPCT platelet were hemostatically equivalent to

the control platelets

La Sicurezza Trasfusionale – Milano, 8 Aprile 2009

SARS : un patogeno emergente Implicazioni per la sicurezza del sangue

Amotosalen photochemical inactivation of severe acute respiratory syndrome coronavirus in human platelet concentratesD. Pinna*, A. Sampson-Johannes†, M. Clementi‡§, G. Poli*§, S. Rossini¶, L. Lin† and E. Vicenzi* 1

Transfusion Medicine. 2005, 15. 269-276

HSR: experimental evaluation


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L’epidemia di SARS é stata contenuta, tuttavia….

Non ci sono farmaci antiviraliNon c’è un vaccinoNon è stato identificato l’ospite

naturaleNessuno può garantire che non

possa riemergereSARS Coronavirus è presente nel è presente nel

sangue degli individui infettatisangue degli individui infettati


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Inattivazione di SARS-CoV HSR1 dopo Trattamento con 150 µM S-59 e 3 J/cm2 UVA in Concentrati Piastrinici

SARS-CoV

Pre-

trattamento

(pfu/mL)

Volume

testato (mL)

Riduzione

(log)

Concentratipiastrinici

N = 5

104.7 100 mL(no virus)

> 7.4


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Inattivazione del SARS-Coronavirus da INTERCEPT

Prima Dopo


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HSR: Clinical evaluation

N. PltX 103/ml

average /range

DoseX 1011

average /range

CI in 1°hX 103/ml

average /range

CCI1°h

Effectiveness

CI 24°hX 103/ml

average /range

CCI24°h

Effectiveness

Temperature Haemorrhage Viral therapy antibiotic therapy

Plateletswith treatment

88625000-17000

3,162,3-3,54

705811400-3000

14/29 40186000-2000

23/29 13/29 2/29 9/29 22/29

Plateletswithouttreatment

100004000-16000

2,721,95-3,5

983715000-4000

18/24 55608500-2500

19/24 1/24 1/24 2/24 17/24

CCI=(Posttransfusion count- Pretransfusion count) X Body surface area (m2)

Platelet dose (x 10 –11)

Effectiveness is proved whenever:•CCI 1° h>7,5 X 109/L •CCI 24° h>2,5 X 109/L


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0

5

10

15

20

25

30

35

40

45

50

1° g 2° g 5° g 6° g

pCO2

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

1° g 2° g 5° g 6° g

pO2

0

20

40

60

80

100

120

140

160

1° g 2° g 5° g 6° g

Glucose


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Dr. E. Castro


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Intercept – Cerus

Mirasol – Navigant



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Mirasol RIBOFLAVIN Vitamin B2 Essential nutrient. RDA ~1.3-1.7mg/d Intake 1>10-50mg/d in food I/V therapy ~ 30-50mg/d Up to 1000mg/d ‘safe’. Plasma level m 24, range 9-79nM [USA]†

LUMICHROME formed naturally in riboflavin solutions Dose in IV preparations. 5-25mg/d Normal plasma level m 11; range 0-75nM [USA] †

Phototherapy of Neonatal Jaundice. ~2-3d @ 420-470nm; 4μW/cm2. Lumichrome etc formed in vivo. Riboflavin supplements given; 300-400 μg/kg/d IV or PO, 4+d

No harmful effects. No excess neoplasia [Olsen et al 1996, Cancer Causes & Control, 7, 411-414; 55120 children followed 16 years]


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The Mirasol PRT system applies light* and riboflavin to reduce the pathogen load in labile blood products by several mechanisms including the three distinct modes of action shown below.

*The Mirasol PRT system uses low wavelength light.

MIRASOL PRT system – Modes of action

In blood products, viral, bacterial, and parasitic nucleic acids absorb low wavelength photons (hν) resulting in nucleic acid damage (direct UV light effect).

Riboflavin interacts with nucleic acids, causing additional irreversible nucleic acid damage through electron transfer chemistry, primarily between riboflavin and guanine.

In all blood products, “Reactive Oxygen Species” (ROS) are generated by riboflavin and light, resulting in irreversible nucleic acid damage through various oxidative reactions.


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Transfer PLT product to Mirasol Illumination bag

1 2 3Add Riboflavin

Solution(2nd sterile dock)

Illuminate for ~ 10 min.

MIRASOL PRT system


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MIRASOL PRT system Summary

• Safe – Use of a natural compound with known safety profile

• Effective against broad range of viruses, bacteria, parasites, as well as white cells

• Simple – Process does not require removal of compounds


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Intercept – Cerus

Mirasol – Navigant



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Theraflex

Short wave UVC ( 254 nm)


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UVC Illumination(< 60 sec)

Storage/Transfusion

Transfer of plasma-reduced platelet concentrates in SSP+

Higly UV trasparent polyolefin acetate bag for irradiation

Theraflex KitTheraflex Kit


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THERAFLEX UV System for Platelets

THERAFLEX Kit (CE certified)

MACOTRONIC UV Illuminator(CE pending)


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Preclinical phase A - efficiency (bacteria, viruses, leucocytes) - platelet quality

Preclinical Phase B - neoantigenes,

- cytokines, parasites

Clin. Phase I study (recov. & survival) Clin. Phase I, full unit, Volunteer,

Tolerance Study Phase III Clinical Study (Thrombocytop. Patients)

CE registration

Status / Planning – THERAFLEX UV Platelets:


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Platelets Red Cells





Psoralen ( S59) Amotosalen

Yes Yes No

Riboflavin Yes Yes ?

UV-C Yes ?


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Platelets Red Cells





Psoralen ( S59) Amotosalen

Yes Yes No

Riboflavin Yes Yes ?

UV-C ? ?

FRALE ( S503) Yes

Inactine Yes


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Tecnologie per l’inattivazione

Rapportocosto/beneficio


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Pathogen reduction: risks versus benefits

Risks Damage to transfusion

product Toxicity to processing

personnel Toxicity to recipient

Benefits Reduction of known

viruses Reduction of bacteria Reduction of parasites Potential reduction of

unknown pathogens Eventually elimination of

lymphocytes


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Inattivazione: si o no ?

opzione scientifica (vincolo etico)

risorse disponibili(vincolo economico)

legge(vincolo legale)

paziente


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Blood Bank: a new perception

Organization providing a community service to patients, hospital and donors

Drug manufacturing firms that produce and distribute a variety of injectable products.

HIV


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Legge 21 ottobre 2005, n. 219 " Nuova disciplina delle attività trasfusionali e della produzione nazionale

degli emoderivati "ORGANIZZAZIONE DEL SISTEMA TRASFUSIONALE

Art. 5. (Livelli essenziali di assistenza sanitaria in materia di attività trasfusionale), i servizi e le prestazioni erogati dalle strutture del Servizio sanitario nazionale in rapporto

alle specifiche competenze disciplinari, con esenzione dalla partecipazione alla spesa, in materia di attività trasfusionali comprendono:

4) esecuzione delle indagini di laboratorio e delle procedure di inattivazione

dei patogeni finalizzate alla certificazione dei requisiti di qualità e sicurezza previsti dalla legislazione vigente per le unità di sangue e gli emocomponenti, con particolare riferimento alla prevenzione delle malattie trasmissibili con la

trasfusione;


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Inattivazione: un problema di economia sanitaria ?

Assessment of the economic value of the Intercept blood system in Belgium. K. Moeremans, Transfusion Medicine, 2006; 16, 17-30

3459200 € - 195364 € Quality Adjusted Life Years (QALY) NAT: 2-3 million per lifeyear

Cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherland. M.J. Postma, Transfusion Medicine 2005; 15, 379-387 554000 € net cost per life year gained (LYG)


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La decisione sulle nuove tecnologie Il ruolo delle Società Scientifiche Consensus Conference – Canada ( 2007)

Is the current risk of transfusion-transmitted disease acceptable in relation to other risk of transfusion ?

What mininum acceptable safety and efficacy criteria should be put into place for the pre-approval assessment of pathogen-inactivated products ?

For PI technologies that have been approvated by the regulatory autorithies, what implications should be considered prior to their widespread adoption ?

Large adequately powered randomized clinical trials should be performed to evaluate and/or to confirm the effectiveness of any new PI technology. Post-licensure phase IV studies should be integrated with haemovigilance systems to enhance the ability to detect adverse events.


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The Canadian Consensus Conference on Pathogen Inactivation in March 2007

During the Consensus Conference on Pathogen Inactivation the consulting panel of experts recognized that based on the relatively low rates of post-tranfusion infections with the most well-known agents (e.g. HIV or HBV), pathogen reduction cannot be recommended.

However, the same panel acknowledged that emerging pathogens have been detected in blood donors at an increasing rate since the HIV epidemic.

The strategy of surveillance, identification and development of test, allows a new agent spread widely even before the disease can be recognized. Such situations undermine confidence in the safety of blood supply when they reach public opinion


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A proactive approach in accordance to the precautionary principle would lead to the reduction of the theoretical risk, and help to sustain public confidence in the blood supply.

The precautionary principle is a different way of making decsion to manage great risks when there is significant scientific uncertainity, to meet society expectations that the risk is covered.

The panel believes that pathogen inactivation should be implemented, when feasible technologies were available and were capable of inactivating a broad spectrum of infectiuos agents


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Quality in the clinical use of blood products implies administring the right quantity of the right blood product in

the right way at the right time to the right patient, and appropriate documentation of

process and the outcome

Blood safety in the European Community:

An initiative for optimal Use 20-22 May 1999, Germany

L’inattivazione dei patogeni: una nuova sfida per la nostra mission


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Thank you

….Waiting for the future of

tranfusion medicine ………

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